OCT-morphometric and genetic predictors of the malignant transformation in melanocytic intraocular tumor

Aim. To determine OCT-morphometric and genetic predictors of the malignant transformation in melanocytic intraocular tumors.

Material and methods. 81 (84 eyes) previously untreated patients with melanocytic intraocular tumors were examined. All patients underwent standard ophthalmological examination and special instrumental diagnostic assessment (ultrasound examination (US), enhanced depth imaging (EDI) optical coherence tomography (OCT), OCT angiography). The bilateral form was diagnosed in 2 (2.4%) patients: in the first case, the benign and suspicious choroidal nevi were detected in the paired eye, in the second case, small choroidal melanoma in both eyes. Multifocal lesions were determined in 3 (4%) patients: in the first case, foci with small melanoma and suspicious choroidal nevus were diagnosed. In the second and third cases, two and three foci with a benign choroidal nevus were identified. Patients were assigned to the following groups: 1st group – with benign choroidal nevus (n=26 foci; mean age 61.1±13.6 years). Gender distribution: female – 18, male – 5. Multifocal lesions were diagnosed in 2 patients (2 and 3 lesions). Thus, the study included 26 benign choroidal nevi. US showed no detectable tumor. 2nd group consisted of patients with suspicious choroidal nevus (n=24 foci; mean age 55±13 years). Gender distribution: female – 22, male – 3. Mean tumor thickness was 0.5±0.1 mm, basal diameter – 5.4±1.9 mm. 3rd group – small choroidal melanoma (n=37 foci; mean age 56.2±14.8 years). Genotyping was performed by high resolution melting analysis. Gender distribution: female – 27, male – 9. Average tumor size according to US was 1,3±0,4 mm (thickness) and 6.9±2.1 mm (basal diameter). All patients underwent laser treatment (n=36) and brachytherapy (n=1). To exclude distant metastases, the patients underwent contrast-enhanced magnetic resonance imaging of the abdominal organs and computed tomography of the chest. Mutations in GNAQ/GNA11 oncogenes were detected using the high resolution melting and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses. The control group was a cohort of individuals without malignancies, comparable in age and sex (n=31).

Results. Comparative analysis revealed statistically significant predictors of benign choroidal nevus progression into a suspicious choroidal nevus, which include convex deformation of the retino-choroidal profile, weakening of hyperreflectivity at the choriocapillaries level, expansion of the peritumoral choroidal vessels and their compression in the central zone, local detachment and severe hyperplasia of the retinal pigment epithelium (RPE), slit-like and local detachment of the retinal neuroepithelium (NE), intraretinal microcysts, disorganization of the photoreceptor structure (p<0.05). In addition, predictors of a suspicious nevus transformation into the small choroidal melanoma were determined, which include choroidal “excavation”, defects in RPE, «shaggy» photoreceptors, accumulation of subretinal hyperreflective deposits (p<0.05). A quantitative analysis of vascular density at the choriocapillaries level showed an increase in the studied parameters in suspicious choroidal nevus compared with small melanoma and benign nevi (p<0.05), which could be a predictor of tumor growth. A significant increase in the density of perfusion of small choroidal melanoma was revealed when compared with group 2 (p=0.02). A comparative analysis of three groups and the control group revealed that mutations in the GNAQ and GNA11 genes in circulating tumor DNA are significantly more common in patients with small melanoma and choroidal nevi. In the control group, oncogenes in circulating tumor DNA were not detected. In patients with small melanoma and suspicious choroidal nevi, mutations in GNAQ/GNA11 in blood are significantly more common than in patients with benign choroidal nevi (1 and 3 groups; p=0.0004; 1 and 2 groups: p=0.0008). In groups 2 and 3, there were no significant differences depending on the presence of mutations in GNAQ and GNA11 genes (p>0.05), which may indicate a high risk of transformation of a suspicious nevus into choroidal melanoma.

Conclusion. In the present paper, a symptom complex of predictive markers was revealed for the first time using EDI-OCT and OCT-A, including the choroidal and the tumor-associated retinal changes that characterize the progression and malignancy of choroidal nevi. Genetic features in circulating tumor DNA were diagnosed in patients with nevi and small choroidal melanoma. The revealed features can be used for screening in patients with high-risk choroidal nevi, as well as for developing modern approaches to predict the course of choroidal melanoma in the early stages of oncogenesis.

Key words: choroidal nevus, small choroidal melanoma, uveal melanoma, OCT, OCT-A, GNAQ and GNA11 oncogenes

Conflicts of interest. The authors have no conflicts of interest to declare.

Funding. There was no funding for this study